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REVIEW

Orchestrating transcriptional control of adult

Jenny Hsieh1 Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA

Stem cells have captured our imagination and generated GABAergic as well as glutamatergic and dopaminergic hope, representing a source of replacement cells to treat a interneurons, which migrate through the rostral migra- host of medical conditions. Tucked away in specialized tory stream (RMS) and integrate in the niches, stem cells maintain tissue function and rejuve- (OB) (Merkle et al. 2004; Scheffler et al. 2005; Lledo et al. nate organs. Balancing the equation between cellular 2008; Brill et al. 2009). Adult-generated olfactory in- supply and demand is especially important in the adult terneurons contribute to odor discrimination and olfac- , as neural stem cells (NSCs) in two discrete regions, tory (Mouret et al. 2009; Sakamoto et al. 2011; the (SGZ) of the and the Kageyama et al. 2012). In some instances, SVZ NSCs (SVZ) next to the lateral ventricles, can also function as progenitors in the continuously self-renew and differentiate into adult brain (Menn et al. 2006). Although decades have in a process called . Through the in- elapsed between the initial discovery of postnatal mam- terplay of intrinsic and extrinsic factors, adult neuro- malian neurogenesis (Altman and Das 1965) and in vitro genic niches ensure neuronal turnover throughout life, derivation of multipotent NSCs from the adult mouse contributing to plasticity and homeostatic processes in brain (Reynolds and Weiss 1992), fundamental informa- the brain. This review summarizes recent progress on the tion is still lacking, such as the regulatory mechanisms molecular control of adult neurogenesis in the SGZ and controlling the self-renewal and differentiation of adult- SVZ, focusing on the role of specific transcription factors generated neurons. that mediate the progression from NSCs to lineage- Understanding the molecular mechanisms controlling committed progenitors and, ultimately, the generation adult neurogenesis has been the focus of recent studies. In of mature neurons and . the past, much insight has been gained from analyses of the developing brain. In a precise spatial and temporal manner, neural precursors give rise to distinct neuronal In the adult mammalian brain, new neurons are contin- subtypes, followed by glial cell generation (McConnell uously generated in two anatomical regions: the subgran- 1989; Guillemot 2007; Okano and Temple 2009). Similar ular zone (SGZ) of the hippocampal dentate gyrus and the to their embryonic counterparts (Guillemot 2005, 2007), subventricular zone (SVZ) lining the lateral ventricles adult NSCs activate intrinsic programs based on the (Altman and Das 1965; Gage 2000; Alvarez-Buylla and sequential activation of transcription factors. In contrast Garcia-Verdugo 2002; Ming and Song 2005). To ensure to , adult NSCs self-renew and continuous neuronal production while maintaining the differentiate in the context of the mature neural (NSC) pool, the sequential steps of adult environment, and adult-generated neurons and glia ap- SGZ and SVZ neurogenesis are regulated by a multicellu- pear to be produced on demand, rather than on a fixed lar neurogenic niche (Doetsch et al. 1999; Palmer et al. schedule per se. Extrinsic factors such as environmental, 2000; Merkle et al. 2004; Shen et al. 2008). Within the physiological, and pharmacological stimuli modulate adult adult SGZ, stem and progenitor cells differentiate into neurogenesis (van Praag et al. 1999). Interested readers may granule neurons, which receive glutamatergic inputs, in refer to additional reviews on this topic (Mu et al. 2010; addition to (Cameron et al. 1993; Kempermann Ihrie and Alvarez-Buylla 2011; Ming and Song 2011). et al. 2004). Adult hippocampal neurogenesis contributes However, it is unclear how niche-derived signals and sub- to learning and memory and may also be involved in sequent signaling cascades ultimately influence the ex- neuropsychiatric disorders (Noonan et al. 2010; Aimone pression of specific transcription factors to govern the et al. 2011; Sahay et al. 2011; Snyder et al. 2011; Petrik different stages of adult neurogenesis. Besides the role of et al. 2012). NSCs in the SVZ differentiate into mostly transcription factors, additional intrinsic factors that in- clude epigenetic mechanisms such as DNA methylation, histone modification marks, chromatin remodeling, and [Keywords: adult neural stem cells; self-renewal; differentiation; niche; microRNAs are not discussed here, but readers may refer ; subventricular zone; reprogramming] 1Correspondence. E-mail [email protected]. to several recent reviews (Li and Zhao 2008; Hsieh and Eisch Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.187336.112. 2010; Ma et al. 2010; Sun et al. 2011; Jiang and Hsieh 2012).

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Transcriptional regulation of adult NSCs

Below, I present an overview of the neurogenic niche several types of TAPs, which can be identified on the and the specific stages of adult neurogenesis, followed basis of morphology and marker expression (Encinas et al. by a description of the role of transcription factors that 2006; Suh et al. 2007; Lugert et al. 2010). The SRY-box control adult SGZ and SVZ neurogenesis. I also discuss 2 () identifies type 2A cells (as the possibility of targeting transcriptional networks as an well as type 1 cells), which transition to late stage TAPs effective strategy to regulate proliferation and differenti- (type 2B) or (type 3). The major difference ation of adult NSCs for therapeutic repair. I end the review between type 2A, type 2B, and type 3 cells is that type 2B by highlighting outstanding questions that will likely be cells were initially identified in -GFP reporter the focus of future studies. mice and expression of the immature neuronal marker (DCX) in Nestin-GFP+ cells defines the transition between type 2A and type 2B, whereas Nes- Overview of adult SGZ neurogenesis tin-negative type 3 cells express DCX only (Dhaliwal and The first region of the adult brain that continues to gen- Lagace 2011). Finally, there is down-regulation of DCX erate new neurons is the SGZ in the dentate gyrus of the and up-regulation of calretinin and NeuN as immature hippocampus (Fig. 1). Within the SGZ niche are popula- neurons differentiate into mature glutamatergic granule tions of stem and types, which vary in neurons. Newly generated neurons in SGZ will structur- their cell division rates. Slowly dividing or quiescent ally and functionally mature in ;6–8 wk (van Praag et al. NSCs (type 1) have a single radial process that extends 2002; Zhao et al. 2006). through the GCL and express markers such as glial fibril- Signals arising from the microenvironment, including lary acidic (GFAP) and Nestin (Seri et al. 2001; cellular components (e.g., vascular cells, glial cells, and Kempermann et al. 2004; Ables et al. 2010; Mira et al. granule neurons themselves) and noncellular components 2010). Recently, a second class of type 1 cells—charac- (e.g., secreted molecules and the extracellular matrix terized by short, horizontal processes—was identified ½ECM), influence the activity of SGZ NSCs (Palmer (Lugert et al. 2010). Horizontal type 1 cells appear to et al. 2000; Ma et al. 2005, 2009; Tavazoie et al. 2008; divide more quickly; however, the lineage relationship Morrens et al. 2012). In the niche, both neurons and as- between radial and horizontal type 1 cells is unclear. trocytes play an instructive role to promote NSC self- Once quiescent NSCs proliferate, they divide to generate renewal and differentiation (Song et al. 2002; Deisseroth transit-amplifying progenitors (TAPs) that have the potential et al. 2004; Tozuka et al. 2005). Several lines of evidence to differentiate into neurons and astrocytes (Kronenberg indicate that neural progenitor cells respond to neuronal et al. 2003; Kempermann et al. 2004; Lugert et al. 2010; activity in the form of glutamate and GABA as part of Bonaguidi et al. 2011; Encinas et al. 2011). Morphologi- their differentiation program (Deisseroth et al. 2004; cally, TAPs are small cells with short tangential processes Tozuka et al. 2005). In addition to , as- and are often found in clusters in the SGZ. There are trocytes are also a potential source of classical paracrine

Figure 1. Adult neurogenesis in the SGZ of the dentate gyrus within the hippocam- pus. (A) Sagittal view of the rodent brain with the boxed region outlining hippocam- pal formation. (B) Schematic of the hippo- campus with CA1, CA3, dentate gyrus (DG), and hilus regions. (C) The SGZ niche is comprised of radial and horizontal type 1 NSCs (pink), early stage type 2a TAPs (orange), late stage type 3 TAPs (yellow), immature granule neurons (green), and ma- ture granule neurons (blue). The progression from type 1 NSCs to mature granule neu- rons in adult SGZ is a multistep process with distinct stages (labeled on top) and is controlled by the sequential expression of transcription factors (bottom colored panels). (ML) Molecular layer; (GCL) gran- ule cell layer.

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Hsieh niche factors such as Notch, Sonic hedgehog (Shh), bone results in depletion of type 1 cells or precocious differen- morphogenetic (BMPs), and Wnts (Ahn and Joyner tiation of type 1 and type 2 cells into neurons (Ables et al. 2005; Lie et al. 2005; Ables et al. 2010; Mira et al. 2010). In 2010; Ehm et al. 2010; Imayoshi et al. 2010). Interestingly, coculture experiments, astrocytes have been shown to maintenance of Sox2 expression itself appears to require promote neuronal differentiation (Song et al. 2002). Vas- active Notch signaling, as loss of activated Notch in RBP- cular components, including dividing endothelial cells, Jk-deficient mice leads to decreased expression of Sox2 smooth muscle pericytes, and fibroblasts, as well as micro- (Ehm et al. 2010). It remains unclear whether Sox2 is glia, are closely associated with newly generated neurons a direct target of Notch signaling or acts through a parallel and may provide instructive cues to NSCs (Palmer et al. pathway. Alternatively, one direct target of Notch signal- 2000; Goldman and Chen 2011). A direct role for endothe- ing is the basic helix–loop–helix (bHLH) transcription lial in promoting neurogenesis was demonstrated factor Hes5, which colocalizes with Sox2 and could in vitro, providing initial evidence that the coassociation of cooperate with Sox2 to control NSC maintenance (Lugert endothelial cells with NSCs may be causal (Shen et al. et al. 2010). 2004). Together, these studies support the concept of a The paired domain and homeodomain-containing tran- multicellular niche to support adult neurogenesis, in scription factor Pax6 is expressed by both radial and which NSCs respond to instructive signals, allowing their horizontal type 1 NSCs as well as early stage type 2 cells. proliferative expansion and differentiation into mature During development, Pax6 is expressed in radial glia (Gotz cell types. Ultimately, niche-derived signals are relayed to et al. 1998; Englund et al. 2005; Hodge et al. 2008). the NSC genome to control transcription of genes in- Functionally, heterozygote small eye Pax6(Sey/+) mutant volved in self-renewal and differentiation. mice display a reduction in GFAP+ type 1 cells, including fewer proliferating GFAP+/BrdU+ type 1 cells (Maekawa et al. 2005). While these results suggest that Pax6 may Maintenance and cell fate specification of SGZ NSCs have a role in controlling the adult NSC pool, its de- The transcriptional network governing the production of finitive role in adult SGZ neurogenesis is still unknown. new neurons in the adult SGZ is relatively unknown In addition to Sox2, Hes5, and Pax6, several additional compared with embryonic neurogenesis. Next, I present noteworthy transcription factors are expressed in adult some of the transcription factors that control adult SGZ SGZ NSCs. Ascl1, another bHLH transcription factor, is neurogenesis. However, in only a few cases have loss-of- also expressed in both radial and horizontal type 1 NSCs function and/or gain-of-function studies been performed; and the majority of type 2 cells (Pleasure et al. 2000; Kim thus, a common theme that emerges is that their func- et al. 2007, 2008, 2011; Ables et al. 2010). Tamoxifen- tional roles are still unclear. To initiate neurogenesis, inducible fate mapping with an Ascl1CreERT2 knock-in type 1 cells divide to generate TAPs as they turn on the allele was found to specifically mark granule cell expression of a series of transcription factors. One tran- types, but not astrocytes or (Kim et al. scription factor specifically expressed in SGZ NSCs is the 2007, 2011). Interestingly, overexpression of Ascl1 leads SRY-related HMG box (Sox) family member Sox2, which to the generation of oligodendrocytes (Jessberger et al. plays key roles in stem cell self-renewal and development 2008), suggesting that the level of Ascl1 is important in of the nervous system (Lefebvre et al. 2007). Sox2 is controlling fate choice. In spite of these findings, the expressed in both radial and horizontal GFAP+/Nestin+ exact role of Ascl1 in the context of SGZ neurogenesis type 1 cells (Komitova and Eriksson 2004; Suh et al. 2007; has not been determined. Lugert et al. 2010). In early stage type 2a cells, Sox2 Several recent studies also describe the use of inducible colocalizes with dividing PCNA+ cells (Ferri et al. 2004). CreERT2 transgenic mouse models to functionally dis- Recently, many studies have taken advantage of condi- sect the transcriptional mechanisms that control the tional and/or inducible mice in adult neurogenesis re- SGZ NSC pool. The forkhead domain transcription factor search (Dhaliwal and Lagace 2011). In this system, a FoxO3 is expressed in Sox2+ NSCs, and the absence of tamoxifen-dependent CreERT2 recombinase driven by a FoxO3 leads to a failure of NSCs to return to the qui- cell-specific promoter/enhancer (Weber et al. 2001) allele escent state, ultimately leading to the depletion of the is crossed with a floxed allele of the of interest (for NSC pool (Renault et al. 2009). In addition, the RE1 loss-of-function studies) and/or a reporter gene (e.g., silencing transcription factor (REST), also known as ROSA26RloxP-stop-loxP lacZ or GFP) to allow fate map- NRSF, functions to repress the neuronal differentiation ping of Cre-recombined reporter+ cells in the adult SGZ. program in embryonic stem (ES) cells and early embry- Conditional deletion of Sox2 in Sox2-expressing adult onic development (Yamada et al. 2010; Mandel et al. SGZ NSCs (using Sox2-CreERT2) resulted in depletion of 2011; Aoki et al. 2012; Soldati et al. 2012). Recent work type 1 and type 2 cells and a corresponding decrease of from my laboratory found that REST is expressed in type immature DCX+ and BrdU/NeuN+ granule neurons, con- 1 cells, but is down-regulated in a subset of Ascl1+ cells sistent with a critical role of Sox2 in stem cell mainte- and the majority of NeuroD1+ cells (Gao et al. 2011). By nance (Favaro et al. 2009). keeping neuronal genes repressed, REST also serves to One recent study addressed the interesting question of preserve the undifferentiated state and maintain the adult what controls Sox2 expression. In the adult SGZ niche, NSC pool. Finally, the nuclear transcription Notch signaling is involved in the maintenance of type 1 factor TLX is strictly required for proliferation of both cells, as conditional deletion of Notch signaling effectors type 1 and type 2 cells (Niu et al. 2011). Using inducible

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Transcriptional regulation of adult NSCs genetic lineage tracing, TLX-expressing cells contribute promote neuronal differentiation, which is associated to both activated (proliferating) and inactive (quiescent) with up-regulation of DCX and the neuronal microtu- type 1 SGZ NSCs. How do FoxO3, REST, and TLX bule-associated protein MAP2AB (Haslinger et al. 2009). regulate NSC activation? Genome-wide Interestingly, a recent study described Sox11 as playing analyses in FoxO3- and TLX-deficient NSCs suggest that an essential role in adult SGZ neurogenesis as well as in many genes involved in cell proliferation show signifi- reprogramming of astrocytes to neurons, together with cant changes (Zhang et al. 2008; Renault et al. 2009; Niu Sox4 and Neurog2 (Mu et al. 2012). However, in vivo et al. 2011). One possibility is that FoxO3, TLX, and REST conditional ablation of Sox4 and Sox11, while inhibiting may function in an interconnected transcriptional net- neurogenesis, did not alter GFAP expression, suggesting work or operate in separate pathways. that differentiation was unaffected. Hence, the The transition from radial and horizontal type 1 cells to identification of transcription factors required for neuro- neuronal lineage-committed TAPs and neuroblasts is nal versus astrocyte fate in the adult SGZ remains to be marked by the up-regulation of the bHLH transcription determined. factor Neurog2 and the T-box transcription factor Tbr2. In addition, FoxG1, a Winged-Helix transcriptional re- The expression of both Neurog2 and Tbr2 begins in a pressor, is expressed in TAPs, but not quiescent NSCs subset of Sox2+/Pax6+/Ascl1+ type 2a cells and peaks as (Shen et al. 2006). Functionally, FoxG1 appears to be TAPs mature into DCX+ and PSA-NCAM+ type 3 cells, required for postnatal hippocampus neurogenesis. Besides with Neurog2 expression decreasing prior to Tbr2 (Hodge the substantial reduction of the size of the dentate in et al. 2008; Roybon et al. 2009a). While the specific roles FoxG1 haploinsufficient mice, decreased numbers of BrdU+ of Neurog2 and Tbr2 in adult SGZ are currently un- TAPs and PSA-NCAM+ type 3 cells due to impaired neu- known, their critical requirement in glutamatergic gran- ronal differentiation are also observed in FoxG1+/ mice, ule neuron specification during development (Arnold suggesting that FoxG1 is involved in regulating the pro- et al. 2008; Roybon et al. 2009a) suggests that they may genitor pool as well as maturation of newborn neurons also play important roles in adult SGZ neurogenesis. (Shen et al. 2006). However, additional studies of adult NSC-specific deletion of FoxG1 are required to fully ex- plore the cell-autonomous role of FoxG1 in adult SGZ Differentiation, survival, and maturation of dentate neurogenesis. granule neurons Besides NeuroD1, several additional transcription fac- As TAPs commit to neuronal lineages and further differ- tors have been shown to be necessary for the survival and entiate into glutamatergic granule neurons, there is a maturation of newly generated granule neurons. The switch in the transcription factor program to control the widely used marker for granule neurons is the prospero- later stages of neurogenesis. In line with this, work from related gene Prox1 (Liu et al. 2000), which is several laboratories showed that the bHLH transcription first up-regulated in late stage type 3 cells and continues factor NeuroD1 is not detected in the majority of GFAP+ to be expressed in immature as well as mature granule type 1 cells, but is only expressed in a rare subset of Sox2+ neurons (Jessberger et al. 2008). In addition to being a NSCs (Steiner et al. 2006; Gao et al. 2009; Kuwabara et al. useful marker of granule neurons, Prox1 is required for 2009). Instead, NeuroD1 expression peaks in late stage the survival and maturation of adult-generated neurons Nestin+/DCX+ type 2b and DCX+ type 3 cells. Condi- (Lavado et al. 2010; Karalay et al. 2011). Conditional tional deletion of NeuroD1 in Nestin+ adult SGZ NSCs deletion of Prox1 in adult Nestin-expressing NSCs leads results in fewer adult-generated granule neurons due to to decreased numbers of DCX+ and calretinin+ granule the essential role of NeuroD1 in the differentiation and neurons (Lavado et al. 2010), and these results were survival of neuronal precursors (Gao et al. 2009). Inter- further confirmed by lentivirus-mediated shRNA knock- estingly, in a subset of NeuroD1-deficient cells, NeuroD1 down in adult SGZ demonstrating reduced numbers of appears to be required for the maturation of newborn glutamatergic neurons (Karalay et al. 2011). Similar to neurons. Kuwabara et al. (2009) demonstrated that NeuroD1, the Prox1 gene is also dependent on Wnt/ NeuroD1 transcription is dependent on Wnt/B-catenin b-catenin signaling, since mutation of the two functional signaling and removal of Sox2 repression from the TCF/LEF sites blocks Prox1 promoter expression after NeuroD1 promoter, which is consistent with the down- b-catenin stimulation in luciferase assays (Karalay et al. regulation of NeuroD1 in Sox2+ TAPs. 2011). In contrast, knockdown of Prox1 using an adeno- Sox family transcription factors may also play funda- virus vector in mature neurons apparently does not mental roles in the transition of TAPs to immature and impact their survival, despite its expression in mature mature granule neurons. Sox3, which belongs to the cells, suggesting that Prox1 may play a specific role during SoxB1 subgroup of Sox factors, is expressed in late stage neurogenesis. DCX+ type 3 cells and down-regulated in post-mitotic Finally, the transcription factor cAMP response ele- NeuN+ granule neurons (Wang et al. 2006). Analogously, ment-binding protein CREB is also required for the mat- Sox11, a member of the SoxC subgroup, is also expressed uration and survival of granule neurons (Jagasia et al. in DCX+ TAPs and neuroblasts and down-regulated in 2009). In terms of its role, overexpression of CREB in mature neurons (Haslinger et al. 2009). Evidence for a role progenitor cells enhances the dendritic length and branch- of Sox11 in adult SGZ neurogenesis comes from the ing on immature neurons, while knockdown has the observation that overexpression of Sox11 is sufficient to opposite effect of reducing the number and complexities

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Hsieh of dendritic branches (Jagasia et al. 2009). Interestingly, Shen et al. 2008). In contrast, type B2 cells have astrocytic there is a reduction in NeuroD1+ cells; however, whether features, but do not contact the ventricle. Type C cells, it is the direct transcriptional target responsible for the the progeny of type B cells, rapidly proliferate and are reduction in differentiation and survival of adult granule often found in clusters near blood vessels (Kriegstein and neurons is unknown. Alvarez-Buylla 2009). Similar to type 2 TAPs in the SGZ, type C cells up-regulate Ascl1, Pax6, and the transcrip- tion factor Dlx2 (Brill et al. 2008). Finally, type C cells Overview of adult SVZ neurogenesis give rise to type A neuroblasts, which form migratory The second region in which neuronal production persists chains encased within astrocyte tubes (Lois et al. 1996). throughout life is within the SVZ of the lateral ventricle Over the course of 3 wk, these multiple progenitor cell (Fig. 2). The adult brain lateral ventricles bear a striking types ultimately give rise to a diverse array of neurons, resemblance to the in the embryonic including deep granule interneurons and calbindin+ peri- neuroepithelium (McConnell 1989; Guillemot 2005). In glomerular cells (from ventral/medial SVZ progenitors) the neocortex, radial glia—progenitors with cell bodies and superficial granule interneurons and calretinin+ peri- close to the ventricles and a long radial process that glomerular cells (from dorsal/anterior SVZ progenitors) contacts the pial surface—generate the tremendous di- (Merkle et al. 2007; Lledo et al. 2008). Most of the OB versity of neurons and glia that populate the CNS (Fishell neurons are GABAergic interneurons; however, a recent and Kriegstein 2003; Noctor et al. 2007). Viral-tracing fate-mapping study suggested the existence of glutamateric studies have shown that a subset of radial glial cells sub- juxtaglomerular neurons (Brill et al. 2009), leaving open sequently gives rise to astrocyte-like NSCs (type B1 cells) the question how SVZ NSCs contribute to distinct neuronal that serve as slowly cycling stem cells of the SVZ during subtypes. postnatal and adult stages (Merkle et al. 2004, 2007; Multiple lines of evidence suggest that the planar Spassky et al. 2005). In addition to their astrocytic mor- architecture of the SVZ niche is important to control the phology and ultrastructure, type B1 cells also express behavior of NSCs (Doetsch et al. 1997; Ihrie and Alvarez- markers associated with astroglia, such as astrocyte-specific Buylla 2011). The small apical processes of SVZ NSCs glutamate transporter (GLAST), brain–lipid-binding protein (known as primary cilium) are surrounded by a rosette of (BLBP), GFAP, and nestin (Doetsch et al. 1999; Liu et al. ependymal cells (Mirzadeh et al. 2008). Here, contacts 2006; Nomura et al. 2010). Interestingly, type B1 cells between type B NSCs and neighboring ependymal cells, contain a nonmotile primary cilium that extends into the the CSF, and the vasculature are especially important ventricular cerebrospinal fluid (CSF), suggesting a signal- to maintain self-renewal and proliferation (Ihrie and ing role of the cilium in the regulation of proliferation and Alvarez-Buylla 2011). Within the SVZ niche, ependymal differentiation (Doetsch et al. 1999; Mirzadeh et al. 2008; cells are multiciliated, raising several possibilities regarding

Figure 2. Adult neurogenesis in the SVZ and RMS. (A) Sagittal view of the rodent brain, with the boxed region outlining the SVZ region next to the lateral ventricle (LV). (B) Schematic of the SVZ with ependymal cells (E), blood vessel cells (BV), and distinct stem/progenitor cell types (types B, C, and A). (C) The SVZ niche is comprised of astrocyte-like type B1 and B2 NSCs (pink), type C TAPs (orange), type A neuroblasts (yellow), immature neurons (green), and mature neurons (blue). The progression from type B NSCs to mature neurons in the adult SVZ is a multistep process with distinct stages (labeled on top) and is con- trolled by the sequential expression of tran- scription factors (bottom colored panels).

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Transcriptional regulation of adult NSCs the role of cilia in controlling stem cell activity. These other tumor suppressor genes, including the and motile cilia are slanted in the direction of CSF, which PTEN pathways (Sun et al. 2007; Liu et al. 2008, 2010). contributes to its flow and creates gradients of Slit Incidentally, Bmi1-null mice have impaired self-renewal chemorepellents that guide anterior migration of adult SVZ NSCs (Molofsky et al. 2003). from the SVZ to the OB (Nguyen-Ba-Charvet et al. 2004; Adult SVZ NSCs also appear to be under the control of Sawamoto et al. 2006). Besides affecting the direction of negative regulators, such as the inhibitor of DNA-binding flow, these motile cilia may also function in an antenna- (Id) genes, which encode dominant-negative antagonists like fashion, receiving factors from CSF such as Hedge- of the bHLH transcription factors such as E47 (Benezra hog, Wnt, and PDGF signals, which are thought to be et al. 1990). Recent work using immunofluorescence and important in this region (Corbit et al. 2005; Jackson et al. genetic fate mapping show that high levels of Id1 are 2006; Adachi et al. 2007; Rohatgi et al. 2007). Ependymal found in bona fide type B1 SVZ NSCs that give rise to the cells also express the BMP inhibitor Noggin, which pro- SVZ neurogenic lineage. What is particularly interesting motes differentiation at the expense of self-renewal and is that a gradient of Id1 expression (from high to low) proliferation (Lim et al. 2000). Besides ependymal cells, appears to be important in controlling SVZ NSC self- the ECM and vascular components are important com- renewal, at least in the context of in vitro ponents of the SVZ niche (Kazanis et al. 2010). The basal assays (Nam and Benezra 2009). In vivo deletion of Id1 or face of the SVZ is comprised of an extensive basement Id3, however, does not seem to have a major phenotype, membrane and the ECM, which is composed of laminin, suggesting redundancy or compensatory mechanisms. heparan sulfate proteoglycans, and tenascin-C, and con- Whether acute deletion of Id1 affects adult neurogenesis tacts SVZ cell types (Mercier et al. 2002; Shen et al. 2008; remains to be determined. Kazanis et al. 2010). Similar to the SGZ, the adult SVZ As type B NSCs transition to type C TAPs, Ascl1 also harbors extensive vasculature and close proximity of expression is transiently up-regulated and coexpressed clusters of proliferating NSCs closely associated with in a subset of progenitors with Neurog2. Ascl1 is important blood vessels (Shen et al. 2008; Tavazoie et al. 2008). Evi- to mediate both GABAergic and glutamatergic neuronal dence from recent work has shown that blood vessels phenotypes (Brill et al. 2009). One unique aspect of SVZ provide signals to NSCs for their proliferation and differ- NSCs that distinguishes them from precursors in the entiation, in addition to serving as a scaffold for neuro- SGZ is the ability of glial-restricted progenitors to mi- blast migration (Snapyan et al. 2009; Whitman et al. 2009; grate radially from the SVZ in the subcortical white Kokovay et al. 2010). Collectively, these studies highlight matter, corpus callosum, , and various cortical the importance of a multicellular niche to regulate the areas, where they differentiate into astrocytes and oligo- self-renewal and differentiation of adult SVZ NSCs. dendrocytes (Marshall and Goldman 2002). The bHLH transcription factor Olig2 is expressed in a subset of SVZ NSCs and appears to be necessary and sufficient to prevent Maintenance and cell fate specification of SVZ NSCs neuronal differentiation and direct SVZ progenitors to- Together, extracellular signaling pathways within the ward astrocytic and oligodendrocytic fates (Marshall et al. SVZ niche and intrinsic programs—including transcription 2005). factors and nuclear receptors—have also been reported to More recently, it was discovered that the dorsal region control SVZ NSC self-renewal and differentiation. Given of the SVZ contains a distinct progenitor population that the fact that SVZ NSCs give rise to both GABAergic and transiently expresses Neurog2 and Tbr2 and gives rise glutamatergic lineages, it is not surprising that adult SVZ to glutamatergic neurons of the OB (Brill et al. 2009). and SGZ neurogenesis is dictated by overlapping tran- Currently, it is unclear whether Neurog2 and Tbr2 play scriptional programs. Sox2 is expressed in TAPs of the functional roles in adult SVZ neurogenesis. Overexpres- SVZ, and loss of Sox2 leads to a marked decrease in pro- sion of Neurog2 in Ascl1+ SVZ progenitors in vitro induced liferating progenitors and reduction of DCX+ neuroblasts the generation of calretinin+ neurons and down-regulated (Ferri et al. 2004; Brill et al. 2009; Roybon et al. 2009a). Ascl1 expression (Roybon et al. 2009b), but the specific Interestingly, a recent study demonstrated that the zinc role of Neurog2 in adult SVZ neurogenesis has yet to be finger protein Ars2 (arsenite-resistance protein 2) is a identified. Conditional inactivation of Tbr2 in the early critical transcriptional activator of Sox2 to maintain adult embryo results in deficits in cortical SVZ neurogenesis SVZ NSCs (Andreu-Agullo et al. 2012). Ars2 was pre- and a complete absence of adult hippocampal neuro- viously known for its conserved role in microRNA bio- genesis. However, Tbr2 does not appear to be required genesis (Yang et al. 2006; Laubinger et al. 2008; Gruber for the establishment of adult SVZ progenitors, since et al. 2009; Sabin et al. 2009). However, this study high- DCX staining in the RMS appears normal (Arnold et al. lights an RNA-independent role of Ars2 in stem cell 2008). Along these lines, Tbr2 expression is down-regu- maintenance. In addition to Sox2 and similar to SGZ lated as neuroblasts exit the cell cycle in the RMS, but is NSCs, FoxO3 and TLX are both expressed in type B SVZ maintained in glutamatergic neurons in the embryo and NSCs and appear to be required for their proliferation and early postnatal stages, suggesting that there may be impor- maintenance (Zhang et al. 2008; Renault et al. 2009; Niu tant contextual differences between the embryo and et al. 2011). Interestingly, Tlx may mediate the repression adult environment (Winpenny et al. 2011). Interestingly, of cell cycle inhibitory factors through the recruitment of Ascl1 is coexpressed with Pax6 in most type C SVZ the Polycomb group protein Bmi-1 as well as a host of progenitors and mediates the GABAergic phenotype,

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Hsieh while coexpression of Ascl1 and Neurog2 is important for Second, will astrocyte- or oligodendrocyte-derived neu- the glutamatergic lineage (Brill et al. 2009; Roybon et al. rons successfully establish functional presynaptic out- 2009a). In contrast, coexpression of Ascl1 and Olig2 is puts and be able to participate in a neural network? required for the oligodendrocyte lineage, suggesting that Indeed, previous studies have shown that astrocytes in Ascl1+ SVZ progenitors are bipotent, with the ability to culture can be reprogrammed to adopt neuronal fates give rise to both neurons and oligodendrocytes (Parras after overexpression of Pax6 alone or the combination of et al. 2004; Roybon et al. 2009a). How different transcrip- Neurog2 and Ascl1 (Heins et al. 2002; Berninger et al. tion factors cross-talk with each other to specify individ- 2007). In particular, transduction of Neurog2 and Ascl1 in ual neuronal and glial subtypes remains to be determined. cortical-derived astroglia resulted in the generation of neuronal cells that fired action potentials and established Differentiation, survival, and maturation of OB neurons functional synaptic connections (Berninger et al. 2007; Heinrich et al. 2010). However, it remains unclear whether To control the later stages of SVZ neurogenesis, NeuroD1 these in vitro generated cells will be capable of integrating begins to be expressed in Tbr2+ TAPs, and its expression into in vivo circuits. is increased in Tbr1+ neuroblasts in the RMS (Roybon Third, even if reprogrammed glia-derived neurons were et al. 2009b). While conditional deletion of NeuroD1 in achieved with the delivery of specific transcription fac- Nestin+ NSCs leads to decreased numbers of OB cells tors, would they generate the correct neuronal subtypes? (Gao et al. 2009), the identity of the NeuroD1-deficient Region-specific fate restriction appears to occur through cells is still unknown. Consistent with the role of NeuroD1 intrinsic mechanisms. For example, cortical astrocytes in the differentiation and/or survival of OB neurons, a from , a region derived from the dorsal recent study used NeuroD1-specific shRNAs to knock telencephalon, may be restricted toward glutamatergic down NeuroD1 levels and found a loss of GABAergic neuronal fates (Heinrich et al. 2010). Therefore, the ques- neurons in the OB (Boutin et al. 2010). Tbr1 expression is tion of whether reprogramming with neurogenic transcrip- transiently expressed in late stage neuroblasts and im- tion factors (or the removal of transcriptional repressors mature neurons during SVZ neurogenesis. Most Tbr1+ such as REST) can overcome this region-specific bias to neuroblasts are post-mitotic and coexpress DCX. From generate both glutamatergic and GABAergic neurons may lineage-tracing studies. Tbr1+ neuroblasts eventually be- be critical for restoring the balance in a damaged nervous come short axon periglomerular neurons (Brill et al. system. 2009). Future studies with conditional knockout alleles One final important question is whether reprogram- will determine whether there is a hierarchy of transcrip- med neurons will be compatible with the host once they tion factors required to promote OB neurogenesis or are integrated into mature neural circuits. Recently, the whether there are separate or redundant transcription reprogramming of fibroblasts from Rett syndrome and programs underlying lineage-specific and context-de- schizophrenia patients into human induced pluripotent pendent neuronal differentiation in adult neurogenic stem cells (iPSCs) has provided potential new avenues to niches. model disease pathogenesis (Marchetto et al. 2010; Brennand et al. 2011). Moreover, iPSCs derived from patients may provide platforms for high-throughput drug screening. Challenges and strategies for nervous system repair Despite these exciting findings, iPSCs are not completely As mentioned in the beginning of this review, the equal to ES cells in various ways, such as in their gene capacity to self-renew gives adult NSCs the potential to expression signatures, copy number variation, coding mu- treat a variety of human neurological conditions, includ- tations, and epigenetic modifications, which could affect ing neurodegenerative diseases, , and immune tolerance (Zhao et al. 2011). For example, genome- (Lindvall et al. 2004; Parent et al. 2007; Kernie and Parent wide DNA methylome analysis has demonstrated differ- 2010). Ultimately, stem is likely to be a ences in DNA methylation between ES cells and iPSCs, combination of exogenous stem cell transplantation and which may have an impact on gene expression and genomic endogenous stem cell fate conversion (Lindvall et al. 2004; stability (Lister et al. 2011). Clearly, these important Goldman 2005). The pioneering work of Blau et al. (1985) differences need further exploration before translating and, more recently, Takahashi and Yamanaka (2006) has iPSCs to the clinical setting. illustrated that reprogramming of differentiated cell types to stem-like cells or, alternatively, from one lineage cell Concluding remarks type directly into a different lineage cell type is achievable. To exploit the utility of transcription factor reprogramming In summary, adult SGZ and SVZ neurogenesis is regu- for nervous system repair, there are several overarching lated at two general levels: (1) niche-derived cell-extrinsic questions that need to be addressed. factors that signal in an autocrine and/or paracrine First, what is the desired cell of origin? Reprogramming manner and (2) integration of niche-derived signals by glia (e.g., astrocytes or oligodendrocytes) as an endoge- transcription factors to control NSC self-renewal and nous cellular source for neuronal repair may be desirable, differentiation. Each of these mechanisms and their since there are many glial progenitors that become acti- associated networks are used to varying degrees during vated and proliferate after injury (Kondo and Raff 2000; different stages of adult NSC self-renewal and differenti- Mangin and Gallo 2011; Robel et al. 2011). ation. Despite the ability of the brain to activate adult

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SGZ and SVZ NSCs, these collective endogenous mech- References anisms are still inadequate to fully restore neuronal pro- Ables JL, Decarolis NA, Johnson MA, Rivera PD, Gao Z, Cooper duction and function to the adult nervous system following DC, Radtke F, Hsieh J, Eisch AJ. 2010. Notch1 is required for damage or injury. A set of therapeutic targets will involve maintenance of the reservoir of adult hippocampal stem strategies for preserving the NSC pool, directing NSCs and cells. J Neurosci 30: 10484–10492. TAPs to adopt a neuronal fate, suppressing glial fates, and Adachi K, Mirzadeh Z, Sakaguchi M, Yamashita T, Nikolcheva promoting differentiation and survival of immature neu- T, Gotoh Y, Peltz G, Gong L, Kawase T, Alvarez-Buylla A, rons. 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This work was supported by the National Institutes Neurosci 12: 1524–1533. of Health grants R01 AG032383, R01 NS076775, and R21 Cameron HA, Woolley CS, McEwen BS, Gould E. 1993. Differ- MH09471501; the Cancer Prevention and Research Institute of entiation of newly born neurons and glia in the dentate gyrus Texas grant (RP100674); and the Welch Foundation (I-1660). of the adult rat. 56: 337–344.

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Orchestrating transcriptional control of adult neurogenesis

Jenny Hsieh

Genes Dev. 2012, 26: Access the most recent version at doi:10.1101/gad.187336.112

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